February 1, 2023

Cryo-EM Reveals How “911” Molecule Helps Repair DNA Damage

The image portrays how the 911 clamp is filled onto DNA. Credit: Courtesy of Dr. Huilin Li, Van Andel Institute
When something fails throughout DNA replication, cells call their own version of 911 to pause the process and fix the problem– a failsafe that is critical to keeping health and warding off illness.
Now, researchers at Van Andel Institute and The Rockefeller University have for the very first time exposed how a crucial piece of this repair work procedure– appropriately called the 911 DNA checkpoint clamp– is hired to the site of DNA damage. The findings, published today in Nature Structural and Molecular Biology, light up new insights into the method cells make sure genetic guidelines are effectively passed from one generation of cells to the next. The task was led by the studys co-corresponding authors Huilin Li, Ph.D., of VAI, and Michael E. ODonnell, Ph.D., of The Rockefeller University and Howard Hughes Medical Institute.
” DNA damage can have extreme effects, consisting of cancer and other illness. Because of this, our cells have a host of checks and balances to make sure DNA stability,” Li said. “Our high-resolution structure of the 911 DNA checkpoint clamp as it communicates with the molecule that loads it onto the DNA hair provides us a comprehensive take a look at the vital process of DNA repair work. We hope these insights can be leveraged toward the advancement of new restorative strategies for illness connected to DNA damage.”

Now, scientists at Van Andel Institute and The Rockefeller University have for the very first time revealed how a crucial piece of this repair work procedure– properly called the 911 DNA checkpoint clamp– is recruited to the site of DNA damage. Due to the fact that of this, our cells have a host of checks and balances to make sure DNA stability,” Li said. “Our high-resolution structure of the 911 DNA checkpoint clamp as it interacts with the particle that loads it onto the DNA strand gives us a detailed look at the essential process of DNA repair. When DNA damage is detected, the ring-shaped clamp is packed on the DNA and transported to the website of the error. In the case of the 911 DNA checkpoint clamp, cryo-EM also revealed a surprise: rather than packing onto DNA from the 3 (or “three prime”) end like all other recognized DNA clamps, the 911 clamp is packed onto DNA from the opposite end, called the 5 (” five prime”) end.

Every day, billions of cells in the human body are replaced through cellular division, a procedure by which one cell splits into two. This basic function drives growth and helps with maintenance of tissues such as skin and muscle. A main part of this system is DNA replication, in which our hereditary guideline manual is carefully duplicated to ensure each cell has an accurate copy.
DNA damage can result from errors in this process or through other aspects that directly harm DNA, such as direct exposure to UV light from the sun or carcinogens such as tobacco smoke. When damage happens, cells have emergency action systems to either stop replication until the issue can be repaired or to kill the cell, thus preventing the incorrect info from being handed down.
This is where the 911 DNA checkpoint clamp is available in. When DNA damage is identified, the ring-shaped clamp is loaded on the DNA and carried to the website of the mistake. Once there, it sends a signal to stop cell division while also flagging other repair work particles to remove the broken DNA and change it with a remedied series.
The structure was figured out through use of VAIs cryo-electron microscopes (cryo-EM), which allow researchers to visualize molecular structures at the atomic level. When it comes to the 911 DNA checkpoint clamp, cryo-EM likewise revealed a surprise: rather than filling onto DNA from the 3 (or “3 prime”) end like all other known DNA clamps, the 911 clamp is loaded onto DNA from the opposite end, called the 5 (” 5 prime”) end. This unexpected and novel finding reshapes what we understand about DNA duplication and sets the phase for more research studies in this location.
Referral: “DNA is loaded through the 9-1-1 DNA checkpoint clamp in the opposite direction of the PCNA clamp” by Fengwei Zheng, Roxana E. Georgescu, Nina Y. Yao, Michael E. ODonnell and Huilin Li, 21 March 2022, Nature Structural & & Molecular Biology.DOI: 10.1038/ s41594-022-00742-6.
Other research study authors are Fengwei Zheng, Ph.D., of VAI; and Roxana E. Georgescu, Ph.D., and Nina Y. Yao, Ph.D., of The Rockefeller University. Cryo-EM data were collected in cooperation with VAIs Cryo-EM Core and the David Van Andel Advanced Cryo-Electron Microscopy Suite.
Research reported in this publication was supported by Van Andel Institute (Li), The Rockefeller University (ODonnell) and the National Institute of General Medical Sciences of the National Institutes of Health under award nos. R01GM115809 (ODonnell) and R35GM131754 (Li); the Breast Cancer Research Foundation under award no. 20-068 (ODonnell); and Howard Hughes Medical Institute (ODonnell). The material is entirely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other granting companies.
About Van Andel Institute.
Van Andel Institute (VAI) is committed to improving the health and improving the lives of present and future generations through cutting edge biomedical research and ingenious instructional offerings. The Institutes scientists study the origins of cancer, Parkinsons and other illness and equate their findings into advancement avoidance and treatment techniques.

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